As a post-doctoral fellow in molecular genetics, Dr. Patrick Gaffney has played a major role in a large scale collaborative project between the Institute of Human Genetics and Department of Medicine which seeks to identify susceptibility loci within the human genome for systemic lupus erythematosus (SLE). The hypothesis driving these studies is that SLE is a complex genetic disease, with inheritance of a few genes conferring susceptibility. Our laboratory has recently completed a genome screen in 105 SLE sib pair families, and has identified potential susceptibility intervals on chromosomes 6, 14, 16, and 20. The aim of the current proposal is to examine the region on chromosome 20 in detail, using a large collection of sib pairs with SLE and their available parents. Evidence for linkage to chromosome 20 has also been demonstrated in an independent cohort of multiplex families by our colleagues at the Oklahoma Medical Research Foundation (OMRF) making this chromosome highly attractive for further fine-mapping efforts. Highly informative short tandem repeat polymorphisms (STRPs) will be utilized to confirm linkage and subsequently narrow the region of interest. When linkage is confirmed and further refined, potential candidate genes in the area will be screened by direct sequencing for mutations or polymorphisms. If the candidate gene effort is not fruitful, we will proceed with construction of a physical map of the region and isolation of novel genes. The long term goal of this project is to identify genes that confer susceptibility to SLE, which should provide a framework for understanding the etiology of the disease and subsequently developing novel effective treatments. Dr. Gaffney's career goal is to be an independent academic physician-scientist. Dr. Tim Behrens, the proposed sponsor, has extensive experience in molecular biology and immunology and has a special interest in the genetics of SLE. The co-sponsors of this proposal, Drs. Dick King and Steve Rich, will provide expertise in the molecular genetics of complex disease and in genetic statistical analysis. The academic milieu at the University of Minnesota, together with the assembled group of sponsors, will provide the high quality training environment necessary for Dr. Gaffney's development into an independent investigator.